The majority of patients with low renin essential hypertension (LREH) secrete a "normal" amount of aldosterone that is inappropriate for their suppressed plasma renin activity. the proposed research will investigate possible mechanisms of this inappropriate aldosterone secretion. Potentiation of aldosterone response to its known stimuli could participate in the pathogenesis of this condition. Some patients with hypertension, including LREH, idiopathic hyperaldosteronism, and normal renin hypertension had an exaggerated response to angiotensin II or ACTH infusions. There is also considerable evidence for an unknown aldosteronotropic factor of pituitary origin other than ACTH. However, it is also possible that the unrecognized factor may be pituitary-dependent rather than secreted directly by the pituitary. We have discovered that angiotensin binding and stimulation of aldosteronogenesis was significantly increased in bovine adrenal glomerulosa cells incubated with androgens or with plasma from patients with LREH. These effects were seen after the androgens or LREH plasma were added to cells and then washed away. When androgens were present, angiotensin actions were inhibited. This resembled other hormone systems in which continuous or discontinuous exposure to modifiers caused opposite responses. These findings suggest a possible explanation for the inappropriate aldosterone secretion in most patients with LREH. We propose to screen plasma from LREH patients, steroids, and sterols for effects on the stimulation of aldosterone secretion by angiotensins. Agents found to modulate responses to angiotensins will be tested in detail. Specificity will be assessed by effects of these proposed modulators on glomerulosa cell response to other aldosterone stimuli and on response of bovine adrenal fasciculata cells to ACTH. We will investigate the mechanisms of action of proposed modulators, focusing on membrane fluidity, hormone binding, phospholipid turnover and calcium fluxes, and pathways of steroidogenesis. Effects of pulsatile treatment of bovine cells with putative regulators will be examined. Modulators will be administered to rats and dogs to assess their effects on angiotensin actions. Finally, we will attempt initial characterization of the potentiating factor in LREH plasma. These studies may uncover new mechanisms in the pathogenesis of LREH.